tbuckley/cabot-search huggingface dataset:
Abstract 1820: Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models
Authors: Simon Skjøde Jensen, Esben Christensen, Martin Bak Winther, Anders Elias Hansen, Jonas Rosager Henriksen, Thomas Lars Andersen, Morten Just Petersen, Svetlana Panina
Journal: Cancer Research (2023)

Abstract TLR7 agonists have shown efficacy in pre-clinical cancer models, however, their clinical use is restricted to topical treatment due to a high systemic toxicity. We have developed a micellar formulation of the TLR7 agonist MBS8(1V270) which demonstrated low toxicity and high efficacy in multiple murine cancer models when administered intravenously as monotherapy. In combination treatment, MBS8(1V270) showed a synergistic effect with PD-1 and PD-L1 inhibitors. Moreover, in several models resistant to anti-PD-1 treatment, MBS8(1V270) co-administration restored sensitivity to anti-PD-1 thus indicating potential for combination treatment in clinical setting. GLP toxicology studies in SD rats and cynomolgus monkeys did not reveal significant toxicities up to the human equivalent dose level of ~1.3 mg/kg which is above anticipated therapeutic dose. Additionally, ex vivo stimulation of human whole blood demonstrated significantly lower IL-6 induction by MBS8(1V270) as compared to the benchmark drug resiquimod. Tissue distribution and excretion of MBS8(1V270) was investigated in SD rats. No signs of drug accumulation were observed in any of the analyzed organs with nearly complete clearance of the drug 24 hours post-end of infusion. The major route of the MBS8(1V270) elimination was via faeces. Cellular uptake of MBS8(1V270) by human blood cells was investigated ex vivo using whole blood from healthy donors. The main cell populations taking up the drug were monocytes and B cells followed by NK cells. No MBS8(1V270) was detected in neutrophils or T cells.In conclusion, MBS8(1V270) was well tolerated in rodents and cynomolgus monkeys at dose levels above therapeutic effective doses identified in mice, thus providing a good therapeutic window. It showed significant anti-cancer activity in multiple murine tumor models when administered either alone or in combination with PD-1/PD-L1 inhibitors. Together, these data provide a rationale for clinical studies of MBS8(1V270) as monotherapy and in combination with immune checkpoint inhibitors. MBS8(1V270) is currently under clinical investigation in the clinical trial MBS8-101 (ClinicalTrials.gov identifier NCT04855435). Citation Format: Simon Skjøde Jensen, Esben Christensen, Martin Bak Winther, Anders Elias Hansen, Jonas Rosager Henriksen, Thomas Lars Andersen, Morten Just Petersen, Svetlana Panina. Efficacy and safety of the TLR7 agonist micelles MBS8(1V270) tested in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1820.
Abstract 6146: Tumor suppressor p73 primes extrinsic apoptosis via transcriptional activation of DR5 and c-FLIP
Authors: Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract The tumor suppressor p73 is a member of p53 family. p73 transcriptionally activates p53-targeted genes involved in cell cycle regulation and apoptosis. It is well known that p73 induces cellular apoptosis via the intrinsic apoptotic pathway upon cellular stresses. However, the role of p73 in extrinsic apoptosis is poorly studied. We observed cell cycle arrested at the G1 phase in cells infected with a p73-expressing recombinant adenovirus (Ad-p73). We observed that overexpression of p73 upregulated c-FLIP at the protein level, in addition to DR5 and p21. c-FLIP is an anti-apoptotic factor that inhibits caspase 8/10 activation, thus blocking extrinsic pathway apoptosis. We demonstrated that c-FLIP is a transcriptional target of p73 based on our observations that: 1) p73 increases c-FLIP at mRNA level, 2) p73 binds to the c-FLIP promoter and 3) p73 enhances c-FLIP promoter-driven luciferase expression. We sought to explore whether the upregulation of c-FLIP prevents extrinsic apoptosis in cancer cells following p73 activation. To address this question, p73 was overexpressed in cells by adenovirus infection and c-FLIP was knocked down by siRNA. Overexpression of p73 induced cellular apoptosis in the cells with knockdown of c-FLIP and this effect was blocked by knockdown of caspase 8. Our results suggest that p73 induces extrinsic apoptosis when c-FLIP is depleted in cancer cells. We further found that the knockdown of DR5 inhibited p73-induced apoptosis in c-FLIP-deficient cancer cells. By contrast, PUMA knockdown did not block p73-induced apoptosis. Our results suggest that DR5 is required for cell extrinsic apoptosis in c-FLIP-deficient cancer cells upon p73 activation. p21 is the cyclin dependent kinase inhibitor that leads to cell cycle arrest at the G1/S phase. Knockdown of p21 enhanced cleaved-caspase 8 and cleaved-PARP in c-FLIP-depleted cancer cells treated with Ad-p73. Our results, taken together, suggest that the p73 primes extrinsic apoptosis via DR5 and the priming level appears to be titrated at the level of c-FLIP. Upregulation of c-FLIP decreases the priming level, resulting in cells converting to cell cycle arrest and survival via p21 whereas reduction of c-FLIP leads the primed cancer cells to undergo extrinsic apoptosis upon p73 treatment in cancer cells. Our discovery of p73 transcriptional upregulation of c-FLIP provides a rationale for depleting c-FLIP to improve antitumor efficacy of p73-targeting cancer therapy. Citation Format: Shengliang Zhang, Wafik S. El-Deiry. Tumor suppressor p73 primes extrinsic apoptosis via transcriptional activation of DR5 and c-FLIP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6146.
Abstract 6203: CTC1-STN1-TEN1 (CST) complex-independent roles for STN1 in DNA double-strand break repair in pancreatic ductal adenocarcinoma
Authors: Changxian Shen, Linlin Yang, Sergio Corrales-Guerrero, Sindhu Nair, Terence Williams
Journal: Cancer Research (2023)

Abstract KRAS mutation occurs in 90-95% of pancreatic ductal adenocarcinoma (PDAC) and is a driver of PDAC; however, the underlying molecular mechanisms by which KRAS mutation maintains survival and promotes progression of PDAC need further refinement. We herein report that KRAS mutations increase STN1 (also named OBFC1) expression leading to enhanced repair of DNA double strand breaks (DSBs) in PDAC. Analysis of The Cancer Genome Atlas databases reveal that STN1 is significantly upregulated in PDAC tissue and, is associated with KRAS mutation and poor survival. Silencing KRAS or pharmacologic inhibition of KRAS signaling decreased STN1 expression in PDAC cells. Canonically, STN1 forms a CST (CTC1-STN1-TEN1) complex, which is important for telomere duplication and maintenance. Intriguingly, siRNA-mediated depletion of STN1 (but not CTC1 or TEN1) sensitized PDAC cells to ionizing radiation and chemotherapy as assessed by radiation clonogenic assay and alamarBlue assay, respectively. Consistently, immunoblotting and immunofluorescence analyses of γH2AX (marker of DNA damage) demonstrated that depletion of STN1 (but not CTC1 or TEN1) resulted in DNA damage. To explore the underlying molecular mechanisms, we performed proteomic analysis and found that STN1 physically interacts with many proteins important for DNA repair, replication and cell cycle progression. Of note, we revealed unreported interactions of STN1 with ATM, ATR and DNA-PKcs, key components of DNA damage response signaling. Furthermore, homologous recombination and non-homologous end joining repair reporter assays demonstrated that STN1 silencing reduced both homologous recombination and non-homologous end joining repair of DSBs in U2OS and PDAC cells. Moreover, flow cytometry and immunofluorescence analyses showed that knockdown of STN1 by siRNA impaired cell cycle arrest at S and G2/M phases which was accompanied with mitotic catastrophe in response to ionizing radiation. Our findings have revealed novel CST complex-independent roles for STN1 in DSB repair and suggest STN1 is a novel biomarker for PDAC as well as potentially other cancers. Citation Format: Changxian Shen, Linlin Yang, Sergio Corrales-Guerrero, Sindhu Nair, Terence Williams. CTC1-STN1-TEN1 (CST) complex-independent roles for STN1 in DNA double-strand break repair in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6203.
Abstract 1831: A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment
Authors: Jaehyuk Choi, Jinyoung Kim, Yu Yon Kim, Seongju Jeong, Sungmin Bae, Daejin Kim, In Young Choi
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors (CPI) are widely used for cancer immunotherapy. However, the response to CPIs is dependent on phenotype of tumor microenvironment (TME). A cold tumor known as immune-excluded or -desert has shown poor response to CPIs due to an absence of effector T cells in TME. IL-2 analog, which is immune stimulator and able to recruit cancer-fighting cells into TME, may be promising therapeutic partner for overcoming a limitation of CPIs. Previously, HM16390, a long-acting CD-122-enhanced IL-2 analog, exerted dose-dependent anti-tumor activity in low immunogenic B16F10 melanoma mice. Here, we further investigated the immune cells composition in TME following HM16390 treatment and synergistic anti-tumor effect after combination with CPI. B16F10 mice were sacrificed at days 1, 3, and 8 following single subcutaneous administration of HM16390 or 5 consecutive daily administrations of aldesleukin. According to the result, HM16390 transiently increased peripheral cytokines (IFNγ and TNFα) more than aldesleukin. In line with this, we observed that the tumor-infiltrating NK/Treg ratio was significantly increased approximately 19 by treatment of HM16390 while showing 4.2 in aldesleukin treated group at Day 3. Furthermore, tumor-infiltrating CD8+/Treg ratio was also upregulated approximately 74 by treatment of HM16390 while only showing 6.1 in aldesleukin treated group at Day 8. Significantly increased pro-inflammatory molecules such as GrzB and IFNγ were also observed in HM16390 treated group compared to aldesleukin (p&amp;lt;0.01 and p&amp;lt;0.001, respectively). Next, we investigated synergistic anti-tumor effects in combination with CPI. B16F10 mice were repeatedly given HM16390 once a week or aldesleukin 5 consecutive days per week with or without mouse anti-PD1. After four weeks treatment, 25% of B16F10 mice showed complete response by treatment of HM16390, and significantly increased up to 88% by combination with anti-PD1. However, none of the mice showed complete response by treatment of aldesleukin/anti-PD1 combo. In conclusion, HM16390 effectively induced tumor growth inhibition through the activation and tumor infiltration of cytotoxic lymphocytes. This favorable immune alteration in tumor elicited a TME remodeling in which CPI could sufficiently respond. Citation Format: Jaehyuk Choi, Jinyoung Kim, Yu Yon Kim, Seongju Jeong, Sungmin Bae, Daejin Kim, In Young Choi. A long-acting and CD122-enhanced IL-2 analog, HM16390, synergizes with immune checkpoint inhibitor by remodeling an immune cell profile in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1831.
Abstract 6153: Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead
Authors: Santhalakshmi Ranganathan, Alexander Kornienko, Antonio Evidente, Daniel Romo, Joseph Taube
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) has fewer treatment options than other types of invasive breastcancer. Moreover, Epithelial to Mesenchymal Transition (EMT) helps enrichment of cancer stem cells(CSCs) which promotes resistance to chemotherapy. Ophiobolin A (OpA), a drug like small molecule wasrecently found to have anti-CSC properties. Our current study investigated the cell death mechanism(s)induced by OpA in various breast cancer cell lines with respect to epithelial-mesenchymal transition(EMT).The mechanism of cell death elicited by OpA was analyzed by applying inhibitors for specific pathwaysincluding apoptosis, necroptosis and paraptosis and by analyzing markers of cell death using flowcytometry and western blotting. HMLE(R) and HMLE(R)-Twist cell lines were used to assay the role of EMT.The formation of necrosomes was analyzed with exogeneous expression of RIPK3 tagged with greenfluorescence protein (GFP) in HeLa cell line which lacks endogenous RIPK3 expression. The necrosomeformation was identified by formation of puncta using confocal microscopy. Immune compromised SCIDmice were used to analyze the effect of OpA In vivo.The data obtained in the present study indicates that OpA has an increased anticancer effect in TNBCcompared to the estrogen receptor (ER) positive breast cancer cells. Cells having undergone EMT wereshown to have more sensitivity towards OpA when compared to -uninduced cell lines, which is sensitiveto Necrostatin-1, an inhibitor of necroptosis. OpA also diminished the CD44hi/CD24lo population in TNBCcells. However, apoptosis and paraptosis inhibitors failed to rescue cell death which clearly confirms thatOpA induces necroptosis cell death pathway in EMT undergone cells. An increased phosphorylation ofRIPK, a necroptosis protein marker, was observed on OpA treatment compared to the control. OpAtreatment significantly increased puncta TNBC compared to the untreated control cells, furtherconfirming the necroptotic cell death in TNBC. OpA treatment showed a significant tumor regression intumor bearing SCID mice. All together our findings identify that OpA induce necroptosis in EMT-enrichedTNBC. The study further needs an in-depth analysis of involvement of EMT in necroptotic cell death inTNBC.Key words: Triple-negative breast cancer, EMT, Ophiobolin A, Necroptosis, cell deathmechanism Citation Format: Santhalakshmi Ranganathan, Alexander Kornienko, Antonio Evidente, Daniel Romo, Joseph Taube. Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6153.
Abstract 1363: Breast pericytes: A newly identified driver of tumor cell proliferation
Authors: Katelyn Del Toro, Yamhilette Licon-Munoz, William C. Hines
Journal: Cancer Research (2023)

Abstract A crucial problem limiting our progress to a cure for breast cancer is understanding what drives tumor growth. While we are aware that potent regulators of tumor development include non-malignant cells coexisting in tumors, not all cell types are easily recognized—nor have they been examined rigorously as potential contributors to malignancy. An obstacle in approaching this problem has been an inability to isolate and purify each cell type from the tissue. Recently our laboratory developed models of each cell type in the breast, allowing us the opportunity to investigate the contributions of primary cell types to tumor cell growth through co-culture. We have discovered that pericytes secrete a potent factor that drives tumor cell expansion directly— and dramatically more than controls (isogenic fibroblasts). The effects of this factor are dose-dependent, and we find that it is protease- and heat-inactivated. Furthermore, tissue immunostaining reveals that pericytes expand into tumor stroma, where they may interact directly with tumor cells. Single-cell RNA sequencing uncovers the heterogeneity of pericytes, which exist on a perivascular spectrum. Citation Format: Katelyn Del Toro, Yamhilette Licon-Munoz, William C. Hines. Breast pericytes: A newly identified driver of tumor cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1363.
Abstract 1676: PRMT5 regulates the chemoresistnace of ovarian cancer cells
Authors: Yen Thi Do, Jin Young Kim, Seungmee Lee, Tam Thuy Lu Vo, Thi Tuyet Mai Pham, Eunyoung Ha, Chi-Heum Cho, So-Jin Shin, Ji Hae Seo
Journal: Cancer Research (2023)

Abstract Ovarian cancer resistance to chemotherapy accounts for the most therapeutic challenge, leading to the high mortality rate of gynecological cancer worldwide. Meanwhile, cancer stem cells (CSCs) are identified as key features in regulating ovarian chemoresistant cancer. In this study, we first found that PRMT5 was upregulated in paclitaxel (PTX)-resistant ovarian cancer cells compared with non-resistant cancer cells. Then, we determined the oncogenic role of PRMT5 in chemoresistant ovarian cancer by using its potent and selective inhibitor, GSK3326595. Disruption of PRMT5 activity by GSK3326595 or depletion of PRMT5 in PTX-resistant ovarian cancer cells restored the sensitivity to chemotherapeutic drug via triggering cell apoptosis. Then, we also validated that inhibition of PRMT5 decreased cell migration ability through the transition of motile mesenchymal phenotypes into epithelial characteristics. Moreover, PRMT5 inhibitor significantly decreased the number of sphere formation and attenuated the stem cell-like properties in PTX-resistant ovarian cancer cells. Therefore, our study suggests that PRMT5 is a powerful target to overcome resistance to conventional chemotherapy for the treatment strategy in ovarian cancer. Citation Format: Yen Thi Do, Jin Young Kim, Seungmee Lee, Tam Thuy Lu Vo, Thi Tuyet Mai Pham, Eunyoung Ha, Chi-Heum Cho, So-Jin Shin, Ji Hae Seo. PRMT5 regulates the chemoresistnace of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1676.
Abstract 5777: Race as a predictive confounder in the rate of transdifferentiation and drug response in human pancreatic acinar ductal metaplasia
Authors: Corey Melissa Perkins, Jinmai Jiang, Hesam Hakimjavadi, Jason Brant, Zhongyue Zhang, Ji-Hyun Lee, David Quashie, Yating Mao, Jamel Ali, Sarah Kim, Martha Campbell-Thompson, Thomas Schmittgen
Journal: Cancer Research (2023)

Abstract Pancreatic diseases (chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American (AA) community in comparison to non-White Hispanics and Whites. Acinar to ductal metaplasia (ADM), the process by which pancreatic acinar cells transdifferentiate into ductal epithelial cells, is believed to be an initiating event of pancreatic ductal adenocarcinoma. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation amongst these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p &amp;lt; 0.05) in Blacks/AAs (White=16, Hispanic=11, Black/AA=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic cancer. A sigmoid Emax function best captured the longitudinal changes in the percentage of ADM in nonlinear mixed effects modeling analysis performed in Monolix. Covariate analysis on top of the selected model demonstrated that race was the only covariate affecting the individual trajectories in the percentage of ADM. We additionally use nanoparticles to study the biomechanical properties (I.e., viscoelasticity, storage modulus) of the ADM microenvironment which shows a stiffer microenvironment in Blacks/AAs than for the other races (White=4,Hispanic=4, Black/AA=1). Furthermore, we have used a histone deacetylase (HDAC) inhibitor in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/AAs displaying a significant chemoresistance (p &amp;lt; 0.05) to HDAC treatment (White=6,Hispanic=6, Black/AA=3) by utilizing an ADM reversal index (ADMRI). Through further analysis, the plan is to continue procuring human samples from these three races to isolate an ADM-specific biomarker in relation race and drug reversal by studying the expression/activity of pancreatic associated genes by bulk-RNA and single-cell sequencing. Citation Format: Corey Melissa Perkins, Jinmai Jiang, Hesam Hakimjavadi, Jason Brant, Zhongyue Zhang, Ji-Hyun Lee, David Quashie, Yating Mao, Jamel Ali, Sarah Kim, Martha Campbell-Thompson, Thomas Schmittgen. Race as a predictive confounder in the rate of transdifferentiation and drug response in human pancreatic acinar ductal metaplasia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5777.
Abstract 6205: Visualizing dynamics of long non-coding RNA TUG1 in live glioblastoma cells
Authors: Ayaka Minematsu
Journal: Cancer Research (2023)

Abstract Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides that are not translated into proteins. lncRNA TUG1 (taurine upregulated gene 1) is highly expressed in various cancers, including glioblastoma. Previously we found that TUG1 is an essential molecule for cancer cells to cope with excessive replication stress in the S phase. Albeit its importance to cell cycle-related function, how it is dynamically regulated during the cell cycle is entirely unknown. Here, we established a system visualizing endogenous TUG1 molecules in live cells. TUG1 was tagged with stem-loop motifs recognized by a specific binding protein fused with GFP. We tracked TUG1 RNA by the GFP signal for 22 hours in T98G glioblastoma cells and found that the expression started from the later G1 phase. When cells were treated with Hydroxy Urea, a chemical that interferes with replication and increases replication stress, the expression of TUG1 was further upregulated in the S phase within 20 mins. We also observed some TUG1 molecules accumulated in several nuclear locations. It may indicate that TUG1 assembles to protect damaged DNA loci efficiently. Our results suggest that the expression of TUG1 is regulated in a cell cycle-dependent manner and is strongly connected with its function of TUG1. The current live-cell imaging system could help further discover the critical roles of TUG1 in cancer cells. Citation Format: Ayaka Minematsu. Visualizing dynamics of long non-coding RNA TUG1 in live glioblastoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6205.